5-146878727-A-AGCTGCTGCTGCTGCT

Position:

• chr5-146878727-A-AGCTGCTGCTGCTGCT

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

The NM_181675.4(PPP2R2B):​c.-276_-262dupAGCAGCAGCAGCAGC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.097 (713 hom., cov: 0)
  • Exomes 𝑓: 0.10 (6937 hom.)
  • Failed GnomAD Quality Control
• Consequence: PPP2R2B NM_181675.4 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 B:1
• Conservation: PhyloP100: 3.19

Genes affected

PPP2R2B (HGNC:9305): (protein phosphatase 2 regulatory subunit Bbeta) The product of this gene belongs to the phosphatase 2 regulatory subunit B family. Protein phosphatase 2 is one of the four major Ser/Thr phosphatases, and it is implicated in the negative control of cell growth and division. It consists of a common heteromeric core enzyme, which is composed of a catalytic subunit and a constant regulatory subunit, that associates with a variety of regulatory subunits. The B regulatory subunit might modulate substrate selectivity and catalytic activity. This gene encodes a beta isoform of the regulatory subunit B55 subfamily. Defects in this gene cause autosomal dominant spinocerebellar ataxia 12 (SCA12), a disease caused by degeneration of the cerebellum, sometimes involving the brainstem and spinal cord, and in resulting in poor coordination of speech and body movements. Multiple alternatively spliced variants, which encode different isoforms, have been identified for this gene. The 5' UTR of some of these variants includes a CAG trinucleotide repeat sequence (7-28 copies) that can be expanded to 55-78 copies in cases of SCA12. [provided by RefSeq, Jul 2016]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.117 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPP2R2B	NM_181675.4	c.-276_-262dupAGCAGCAGCAGCAGC		5_prime_UTR_variant	1/10	ENST00000394411.9	NP_858061.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPP2R2B	ENST00000394411.9	c.-276_-262dupAGCAGCAGCAGCAGC		5_prime_UTR_variant	1/10	2	NM_181675.4	ENSP00000377933.3

Frequencies

GnomAD3 genomes AF: 0.0968 AC: 14559 AN: 150420 Hom.: 709 Cov.: 0

Gnomad AFR AF: 0.0771

Gnomad AMI AF: 0.0833

Gnomad AMR AF: 0.0788

Gnomad ASJ AF: 0.116

Gnomad EAS AF: 0.0657

Gnomad SAS AF: 0.125

Gnomad FIN AF: 0.0518

Gnomad MID AF: 0.103

Gnomad NFE AF: 0.119

Gnomad OTH AF: 0.0988

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.101 AC: 109718 AN: 1087864 Hom.: 6937 Cov.: 27 AF XY: 0.104 AC XY: 55423 AN XY: 534104

Gnomad4 AFR exome AF: 0.0771

Gnomad4 AMR exome AF: 0.0840

Gnomad4 ASJ exome AF: 0.133

Gnomad4 EAS exome AF: 0.0832

Gnomad4 SAS exome AF: 0.115

Gnomad4 FIN exome AF: 0.102

Gnomad4 NFE exome AF: 0.100

Gnomad4 OTH exome AF: 0.113

GnomAD4 genome AF: 0.0968 AC: 14569 AN: 150536 Hom.: 713 Cov.: 0 AF XY: 0.0940 AC XY: 6901 AN XY: 73432

Gnomad4 AFR AF: 0.0773

Gnomad4 AMR AF: 0.0789

Gnomad4 ASJ AF: 0.116

Gnomad4 EAS AF: 0.0656

Gnomad4 SAS AF: 0.124

Gnomad4 FIN AF: 0.0518

Gnomad4 NFE AF: 0.119

Gnomad4 OTH AF: 0.0968

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Jul 17, 2015

- -

PPP2R2B-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 20, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs10591869; hg19: chr5-146258290;